Adenosine deaminase (ADA) deficiency was the first of the human immunodeficiencies for which the underlying biochemical defect was discovered. Subsequent studies revealed that ADA deficiency is the most severe of the immunodeficiencies, affecting the production of all lymphocyte populations. However, despite many years of investigation the molecular basis of the severe combined immunodeficiency resulting from ADA deficiency is not understood. The principle long-range goal of research proposed here is to understand the role of ADA in the development and function of the immune system. Another long-range goal is to understand the role of adenosine signaling in disease. The pursuit of these goals is facilitated by the availability of ADA- deficient transgenic mice that display most features seen in ADA- deficient humans. In addition to immunodeficiency, ADA-deficient humans and mice are characterized by skeletal abnormalities, renal problems, pulmonary insufficiency, neurological impairment, and (in mice) cardiac hypertrophy. ADA plays a critical role in controlling the concentration of adenosine, thereby potentially affecting many areas of intercellular signaling influenced by adenosine. In the absence of ADA the uncontrolled accumulation of adenosine may lead to widespread activation of adenosine receptors on a variety of cells with detrimental effects on numerous areas of physiology. The other ADA substrate, 2'- deoxyadenosine, may be cytotoxic by interference with a number of critical metabolic pathways. In considering the complexity of the phenotypes associated with ADA deficiency in humans and mice, it is likely that some features are attributable to alterations in adenosine signaling, whereas others are due to 2'- deoxyadenosine-induced metabolic disturbances. ADA-deficient mice have tremendous potential as investigative tools in lymphocyte immunobiology and adenosine signaling. The utility of ADA-deficient mice is aided significantly by the ability to use ADA enzyme therapy as a convenient experimental strategy to regulate the metabolic consequences of ADA deficiency and differentially correct abnormalities associated with ADA deficiency. To address the long-range goals of this research we have organized four specific aims around the following four questions. AIM I. What is the molecular basis of impaired T cell development in ADA-deficient mice? AIM II. What is the impact of ADA deficiency on B cell development and function? AIM III. What is the impact of ADA deficiency on natural killer cell development and function? AIM IV. What role does adenosine signaling play in the non-immune features associated with ADA deficiency?